The Potential Impact of Coinfection on Antimicrobial
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Review The potential impact of coinfection on antimicrobial chemotherapy and drug resistance 1* 2,3* 4 5 6 Ruthie B. Birger , Roger D. Kouyos , Ted Cohen , Emily C. Griffiths , Silvie Huijben , 1,7 8 1,9 1,9* Michael J. Mina , Victoriya Volkova , Bryan Grenfell , and C. Jessica E. Metcalf 1 Department of Ecology and Evolutionary Biology, Princeton University, Princeton, NJ, USA 2 Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zu¨ rich, University of Zu¨ rich, Zu¨ rich, Switzerland 3 Institute of Medical Virology, University of Zu¨ rich, Zu¨ rich, Switzerland 4 Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA 5 Department of Entomology, Gardner Hall, Derieux Place, North Carolina State University, Raleigh, NC 27695-7613, USA 6 ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clı´nic –Universitat de Barcelona, Barcelona, Spain 7 Medical Scientist Training Program, Emory University School of Medicine, Atlanta, GA, USA 8 Department of Diagnostic Medicine/Pathobiology, Institute of Computational Comparative Medicine, College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA 9 Fogarty International Center, National Institutes of Health, Bethesda, MD, USA Across a range of pathogens, resistance to chemothera- One way to classify the diversity of possible interactions py is a growing problem in both public health and animal between pathogens is to set them on a spectrum of syner- health. Despite the ubiquity of coinfection, and its po- gistic to antagonistic. In synergistic interactions, the with- tential effects on within-host biology, the role played in-host growth rate of one parasite will increase in the by coinfecting pathogens on the evolution of resistance presence of the other, while in antagonistic interactions, and efficacy of antimicrobial chemotherapy is rarely the presence of one pathogen will limit the growth rate of considered. In this review, we provide an overview of the other. Examples of the former might include HIV– the mechanisms of interaction of coinfecting pathogens, hepatitis C virus (HCV) [4] and HIV–malaria [5–7]; exam- ranging from immune modulation and resource modu- ples of the latter might be multiple strains of malaria [8]. It lation, to drug interactions. We discuss their potential is also possible that coinfecting pathogens do not interact, implications for the evolution of resistance, providing but as this is unlikely to affect the evolution of resistance it evidence in the rare cases where it is available. Overall, is not discussed further in this review. It should be noted, our review indicates that the impact of coinfection has however, that the degree to which pathogens interact is the potential to be considerable, suggesting that this should be taken into account when designing antimicro- Glossary bial drug treatments. Coinfection: for the purposes of this review, the term coinfection is used in a broad sense, covering all combinations of infection with more than one Classifying mechanisms of pathogen interactions pathogen or strain. We consider coinfections with multiple strains of the same The spread (see Glossary) of chemotherapy-resistant species as well as infections with multiple species of pathogen (following [48]). This includes simultaneous infection (two pathogens or strains transmitted pathogens is a serious global problem [1], affecting our together), superinfection (one pathogen or strain infects a host where another ability to control pathogens ranging from parasites to is already present), and sequential infection (one pathogen or strain infects viruses. Infected individuals are often coinfected, either after a previous infection has cleared, potentially leaving residual changes in the immune or resource landscape that would affect the second pathogen). by multiple strains of the same pathogen or by different Emergence: the emergence of a resistance mutation within a pathogen is species of pathogen. Classic examples include the multi- generally the result of a de novo mutation. For bacteria, other possibilities plicity of strains typically identified in malaria infections include acquisition from other strains or species present in the vicinity of the pathogen, that is, via horizontal gene transfer. [2] and coinfections involving human immunodeficiency Fitness cost: frequently, mutations conferring some degree of resistance are virus (HIV) and Mycobacterium tuberculosis (TB) [3]. Here, associated with a fitness cost in terms of reduced pathogen within-host growth we present an overview of the potential ways by which rate, which translates into a reduction in transmission of the resistant pathogen. Such costs are often mediated by competition with other coinfecting pathogens, coinfection might affect the outcome of chemotherapy, via direct competition, or apparent competition mediated by the immune system. focusing on the question of the evolution of drug resistance. Even mutations that apparently have no cost, for example, mutations involved in conversion of efflux pumps, will be affected by the presence of susceptible Corresponding author: Birger, R.B. ([email protected]). strains, purely in the fraction of transmission dominated. Keywords: drug resistance; coinfection; immune modulation; resource competition; Focal pathogen: we use the term focal pathogen to mean the pathogen initially parasite interactions. targeted for treatment. Often, but not always, this can mean the pathogen * These authors contributed equally. causing either more severe or more recognizable disease. Spread: once a de novo resistance mutation has emerged, it must spread 0966-842X/ within the population. This requires both successful replication within a host, ß 2015 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tim.2015.05.002 and then spread through the population via transmission to other hosts. Trends in Microbiology, September 2015, Vol. 23, No. 9 537 Review Trends in Microbiology September 2015, Vol. 23, No. 9 a Table 1. Interactions at the scale of the individual Beneficial Neutral Detrimental b Beneficial HIV–HCV [4] Helminths beneficial for bacteria/viruses [17,18] Cheating/cooperation in siderophore-sharing bacteria [28,29] c d HIV–TB [3] HIV–GB virus C (detrimental to HIV) [74] Neutral – Non-overlapping: tinea pedis, influenza Fever-promoting: malaria detrimental for syphilis[75], Helicobacter pylori restricting (detrimental for) TB infection [26] Detrimental – – Competing strains: malaria (depending on strains) [38] a Row labels correspond to the impact on one pathogen of the coinfection, while column labels correspond to the impact of the coinfection on the other. b Hepatitis C virus. c Mycobacterium tuberculosis. d Formerly known as Hepatitis G virus or HGV. often unclear, and the available evidence is possibly con- Synergistic interactions: immune-mediated facilitation troversial. The type of interaction broadly determines the When coinfection occurs, one or both pathogens may sup- impact of coinfections on resistance evolution: while syn- press the immune response. This suppression may facili- ergistic interactions tend to promote resistance, antago- tate the spread of drug-resistant mutants of the coinfecting nistic interactions hinder the evolution of resistance (see pathogen via several routes. First, reduced immune-medi- below). ated killing of pathogens may lead to higher pathogen This review is organized around the two main mecha- replication, which can increase the probability of the emer- nisms that might shape the outcome of chemotherapy: (i) gence of de novo resistance (e.g., HIV–malaria coinfection immune modulation (whereby the presence of the coinfect- [5]). Second, the reduced efficacy of the immune system ing pathogen can affect immune function), and (ii) resource may increase the frequency of symptomatic infections (in modulation (where the coinfecting pathogen can have the absence of immunopathology) and hence the use of effects on resource availability for the focal pathogen) – antimicrobials (e.g., HIV–herpes simplex virus 2 coinfec- Table 1 and Figure 1 give examples. For both mechanisms, tion [9]), which will increase the selective pressure for we provide an overview of their potential to affect the resistant mutants and potentially the spread of resistant emergence and spread of drug resistance across a range pathogens. Third, reduced immune-mediated killing may of pathogens, distinguishing between synergistic and an- allow the replication of drug-resistant strains bearing a tagonistic interactions where possible. It is important to high fitness cost (which would otherwise be outcompeted note that for many pathogens, multiple mechanisms may by fitter sensitive strains, e.g., HIV–TB coinfection [10]). apply; additional, less clearly classified mechanisms may Similarly, impaired immune control may increase the also be involved (Boxes 1 and 2). Finally, while there may danger of a recrudescence of partially resistant pathogen be clear evidence of interaction, the exact mechanism in populations after therapy has ended. Such partially resis- play is frequently unknown. tant pathogen populations are often selected for during therapy, and might be present after treatment [11]; with Immune modulation an effective immune response they would be rapidly elimi- Pathogens attacking hosts are confronted by the immune nated, but an immunosuppressive coinfection may allow system, and often the immune responses stimulated by one for their proliferation [12].